Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide. Even after surgery to remove the primary tumor, about one in three patients will experience metastatic relapse, due to a few cancer cells that linger undetected by current clinical tests. This minimal residual disease” (MRD) has been difficult to study, leaving a major gap in our understanding and treatment capacity. Our project set out to identify the cancer cells that survive surgery or chemotherapy, to understand how they evade the immune system, and to reveal new ways to eliminate MRD before it causes relapse. These goals are crucial for society, as preventing metastatic recurrence would reduce mortality, improve quality of life, and lower long-term healthcare costs.
By the end of the project, we have generated innovative pre-clinical models of metastatic relapse that, for the first time, allowed to identify a group of cells, marked by the protein EMP1, as the cell of origin of residual disease and metastatic recurrence. We revealed a window of immune vulnerability that can be exploited with neoadjuvant immunotherapy.
In parallel, we uncovered CRC persister cells that survive chemotherapy, marked by the protein Mex3a. Upon exposure to chemotherapy, CRC cells convert to a plastic, fetal intestine-like program that they share with EMP1⁺ cells.
Cellular plasticity also underlies resistance to targeted therapy with KRAS inhibitors: CRCs evade treatment by switching into a cancer stem-like state. Combining KRAS inhibitors with agents that target cancer stem cells enhanced KRAS-directed therapy, opening a new therapeutic avenue focused on blocking cell plasticity.
Our research on how tumour cells evade the action of the immune system defined a dual barrier imposed by TGF-β signaling on immune cells. First, TGF-β prevents the recruitment of fresh CD8+ T lymphocytes from peripheral blood. Second, it reprograms stromal macrophages to produce the protein osteopontin (encoded by SPP1), which in turn suppresses the proliferation of the T cells. These findings nominate SPP1 as a promising therapeutic target.
Together, these discoveries provide actionable biomarkers, inspire and/or support ongoing clinical trials, and establish cancer-cell plasticity and minimal-residual disease biology as new therapeutic frontiers. The project therefore delivers fundamental insights with immediate translational potential.
